Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/92477
Citations
Scopus Web of Science® Altmetric
?
?
Type: Journal article
Title: GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology
Other Titles: GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology
Author: Krall, J.
Balle, T.
Krogsgaard-Larsen, N.
Sørensen, T.
Krogsgaard-Larsen, P.
Kristiansen, U.
Frølund, B.
Citation: Advances in Pharmacology, 2015; 72:201-227
Publisher: Elsevier
Issue Date: 2015
ISSN: 1054-3589
1557-8925
Statement of
Responsibility: 
Jacob Krall, Thomas Balle, Niels Krogsgaard-Larsen, Troels E. Sørensen, Povl Krogsgaard-Larsen, Uffe Kristiansen, Bente Frølund
Abstract: A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown for only a few orthosteric ligands. Still, these examples show that it is indeed possible to obtain orthosteric subtype selectivity and they serve as models for further development in the orthosteric GABAAR ligand area. This review presents the very few existing structural classes of orthosteric GABAAR antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity.
Keywords: GABAA receptors; GABAA receptor antagonists; GABAA receptor partial agonists; 4-PIOL; Structure–activity relationship studies; Receptor homology models; Tonic inhibition
Rights: © 2015 Elsevier Inc. All rights reserved.
RMID: 0030021080
DOI: 10.1016/bs.apha.2014.10.003
Appears in Collections:IPAS publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.